Blend compositions for oral administration as a rapidly dissolving powder and/or suspension

ABSTRACT

Disclosed is a dry powder oral formulation that includes an active pharmaceutical ingredient (API), a lecithin powder, a galactomannan, one or more sweetening agents, one or more flavoring agents and an organic acid in a pharmaceutically acceptable preparation. Also disclosed are an excipient composition in absence of an API and methods of making and using the formulations and compositions. Also disclosed is a chewable, swallowable, and/or orally disintegrating tablet comprising an active pharmaceutical ingredient (API), a lecithin powder, a galactomannan, one or more sweetening agents, one or more flavoring agents and an organic acid in a pharmaceutically acceptable preparation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application Ser. No. 62/529,170 filed on Jul. 6, 2017, which is incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable.

FIELD

The present invention relates to pharmaceutically acceptable formulations of orally administered substances, and more particularly to formulations for orally administering substances, the individual formulations being administrable in either a dry powder form or with a small quantity of water (as preferred by the subject), and to methods for preparation and administering the substances.

INTRODUCTION

Patient acceptance of medications, often referred to as patient adherence, has been reported to average 50% in developing countries around the world (1). Although a number of factors may contribute to the 50% lack of adherence, characteristics of the drug formulation may be of particular importance. For example, oral tablet formulations can sometimes cause dysphasia and/or nausea and vomiting in patients (2). Further, unpleasant taste may be a challenge in administering a medicine particularly for children (3, 4).

Ibuprofen is a commonly used non-steroidal anti-inflammatory drug (NSAID) with multiple beneficial effects including pain relief and reduction of inflammation and fever. (5, 6). Nevertheless, patient adherence may be a challenge in treatment with ibuprofen as well as other NSAIDs (7, 8).

Additionally, formulations which are administrable both in dry powder form and in suspension by adding a minimum quantity of water to dissolve the dry powder are not available on the market. Powder, solution, and suspension dosage forms typically utilize a different set of excipients to achieve acceptable physical properties. For a powder, excipients are chosen on the basis of achieving acceptable physical properties such as flow, density, and compactibility. For a solution and suspension dosage forms, excipients are chosen on the basis of achieving acceptable properties such as solubility, suspendability, dispersability, and viscosity. For flavored powders, solutions, and suspensions, the type and concentration of sweeteners and flavors are typically different since the sensory perception of flavor and texture would be different when consuming a powder versus a liquid dosage form. Also, taste masking of active pharmaceutical ingredients (API) are typically dependent on type, concentration, and processing method (i.e., API coating, granule coating, etc.) of excipients.

Therefore, what is needed is a formulation which is administrable both in dry powder form and in suspension by adding a minimum quantity of water to dissolve the dry powder.

SUMMARY

Accordingly, the inventors herein have succeeded in devising formulations that can be administered either as a dry powder or in a small quantity of water. The new formulations provide improved taste and mouthfeel to facilitate ease of administration and patient adherence.

Thus, in various embodiments, the present invention is directed to dry-powder oral formulations that include an active pharmaceutical ingredient (API), a lecithin powder, a galactomannan, one or more sweetening agents, one or more flavoring agents and an organic acid in a pharmaceutically acceptable preparation. In various embodiments, the dry-powder formulation includes ibuprofen; sunflower lecithin powder; guar gum; xylitol and isomalt; cherry, strawberry and raspberry flavorings, grape flavoring, orange flavoring, other fruit flavors, and citric acid, malic acid, fumaric acid, or any other acidulants, and combinations of any of the following, in a pharmaceutically acceptable preparation. In various aspects, the formulation solubility or dispersability in water is no more than about 0.5 w/v. In various aspects, the formulation or an aqueous solution or dispersion thereof is in a unit dosage form in a container selected from the group consisting of a blister foil pack, stick pack, sachet, pouch, bottle, orally disintegrating tablet, dispersible tablet, capsule, powder in a capsule, and spheres in a capsule. In various aspects, the unit dosage form of ibuprofen is in a quantity of about 50, about 100, about 200, about 400, about 600 or about 800 mg.

In various other embodiments, the present invention is directed to a method of administering an API. The method includes providing a dry-powder oral formulation of the API, a lecithin powder, a galactomannan, one or more sweetening agents, one or more flavoring agents and an organic acid in a pharmaceutically acceptable preparation. In various embodiments, the dry-powder formulation includes ibuprofen; sunflower lecithin powder; guar gum; xylitol and isomalt; cherry, strawberry and raspberry flavorings and citric acid in a pharmaceutically acceptable preparation. In various aspects, the formulation solubility or dispersability in water is no more than about 0.5 w/v. In various aspects, the formulation or an aqueous solution or dispersion thereof is in a unit dosage form in a container selected from the group consisting of a blister foil pack, stick pack, sachet, pouch, orally disintegrating tablet, dispersible tablet and capsule. In various aspects, the unit dosage form of ibuprofen is in a quantity of about 50, about 100, about 200, about 400, about 600, or about 800 mg.

Various other embodiments are directed to a method of preparing a dry powder oral formulation of an API. The method includes combining, in any order, an API, a lecithin powder, a galactomannan, one or more sweetening agents, one or more flavoring agents and an organic acid in a pharmaceutically acceptable preparation. In various embodiments, the dry-powder formulation includes ibuprofen; sunflower lecithin powder; guar gum; xylitol and isomalt; cherry, strawberry and raspberry flavorings and citric acid in a pharmaceutically acceptable preparation. In various aspects, the formulation solubility or dispersability in water is no more than about 0.5 w/v. In various aspects, the formulation or an aqueous solution or dispersion thereof is in a unit dosage form in a container selected from the group consisting of a blister foil pack, stick pack, sachet, pouch, orally disintegrating tablet, dispersible tablet and capsule. In various aspects, the unit dosage form of ibuprofen is in a quantity of about 50, about 100, about 200, about 400, about 600 or about 800 mg.

In various other embodiments, the present invention is directed to an excipient composition for combining with an API to produce a drug or nutraceutical composition. The composition includes a lecithin powder, a galactomannan, one or more sweetening agents, one or more flavoring agents and an organic acid in a preparation that when combined with an API produces a pharmaceutically acceptable preparation. In various embodiments, the excipient composition includes a sunflower lecithin powder; guar gum; xylitol and isomalt; cherry, strawberry and, raspberry flavorings and citric acid.

In various other embodiments, the present invention is directed to a dry powder formulation or an aqueous solution or dispersion thereof as described above comprised within a unit dosage form in a container selected from the group consisting of a blister foil pack, stick pack, sachet, pouch, bottle, orally disintegrating tablet, dispersible tablet, powder in a capsule, spheres in a capsule, and capsule.

In yet other embodiments, the present invention is directed to a chewable, swallowable, and/or orally disintegrating tablet comprising an active pharmaceutical ingredient (API), a lecithin powder, a galactomannan, one or more sweetening agents, one or more flavoring agents and an organic acid in a pharmaceutically acceptable preparation.

These and other features, aspects and advantages of the present teachings will become better understood with reference to the following description, examples and appended claims.

DRAWINGS

No drawings are submitted with this application.

DETAILED DESCRIPTION

The present invention is directed to formulations for orally administering substances in a dry powder form or with a small quantity of water and to methods for preparing and administering the formulations.

As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.

The term “about” when used before a numerical designation, e.g., pH, temperature, quantity, concentration, and molecular weight, including range, indicates approximations which may vary by ±5%, ±1%, or ±0.1%.

As used in the specification and claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a pharmaceutically acceptable carrier” may include a plurality of pharmaceutically acceptable carriers, including mixtures thereof.

The term “and/or” is intended to mean either or both of two components of the invention.

The term “subject,” “individual” or “patient” is used interchangeably herein, and refers to a human.

The term “device,” as used herein, refers to an apparatus or system capable of delivering a drug to patient in need thereof.

The term “in need of treatment” and the term “in need thereof” when referring to treatment are used interchangeably and refer to a judgment made by a caregiver, e.g. physician, nurse, nurse practitioner, that a patient will benefit from treatment.

The term “pharmaceutically acceptable,” as used herein, refers to a component of a pharmaceutical composition that is compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered and includes, but is not limited to such liquids and powders that are hydrophilic substances, hydrophobic substances and substances that possess both hydrophilic and hydrophobic properties such as emulsifiers.

The term “therapeutically effective amount,” as used herein, refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, or individual that is being sought by a researcher, healthcare provider or individual.

The term “w/w” as used herein, is intended to refer to mass fraction, i.e., the mass of a component divided by total mass of the whole. The term “% w/w” is intended to refer to the mass fraction multiplied by 100. Similarly, the term “w/v” refers to volume concentration, i.e., the mass of a component divided by total volume of the whole and the term “% w/v” refers to the volume concentration multiplied by 100.

The term “mouthfeel’ as used herein is intended to refer to the physical sensations in the mouth produced by a particular food or drug.

The term API (active pharmaceutical ingredient) as used herein, refers to the component in a therapeutic medication or nutraceutical substance that is biologically active.

The term “unit dose” refers to a single drug delivery entity, e.g., a tablet, capsule, dry powder, solution, dispersion etc., that is administered to an individual. The amount administered may vary according to numerous factors, including, e.g., the age of the individual, the weight of the individual, the genetic makeup of the individual, and the severity of symptoms exhibited by the individual to whom the drug is administered.

The unit dosage form (powder, granulation, tablet, sphere, or capsule) may be packaged into a blister foil pack, a stick pack, a sachet, a pouch, a bottle, or any other self-contained unit. The unit dosage form may optionally be packaged as a dual package whereby the dry component (powder, granulation, tablet, sphere, capsule) may be combined with a solution component in an integrated package.

The term “excipient” as used herein is intended to mean components of a drug formulation other than the API that are added to a drug formulation to perform a specific function in the finished drug product. The excipient may aid in dissolution or dispersion of the API, beneficially alter the mouthfeel of the drug product, improve the taste profile of the drug product among other things. An excipient composition is intended to refer to a combination of a plurality of excipients that can be added to an API to produce a finished drug product.

The term NSAID (non-steroidal anti-inflammatory drug) as used herein, refers to drugs distinguished as a class from steroid compounds in which the drugs provide analgesic, antipyretic and anti-inflammatory effects. Prominent NSAIDs include aspirin, ibuprofen and naproxen although other NSAIDs include ketoprofen, sulindac, etodolac, fenoprofen, diclofenac, flurbiprofen, ketorolac, piroxicam, indomethacin, mefenamic, meloxicam, nabumetone, oxaprozin, ketoprofen, meclofenamate, tolmetin and salsalate.

Ibuprofen is an NSAID that is a non-specific cyclooxygenase inhibitor available over the counter and generally viewed as being relatively safe. (9, 10). Ibuprofen is sparingly soluble in water and different formulations have shown different absorption rates but equivalent bioavailability (11).

In various embodiments, ibuprofen may be present in certain formulations herein. In such formulations, the ibuprofen may be present in a quantity of from about 1.5% w/w, about 3.0% w/w, about 4.0% w/w, about 5.0% w/w or about 6.0% w/w up to about 9.0% w/w, about 10.0% w/w, about 11.0% w/w, about 12.0% w/w, about 13.0% w/w, about 14.0% w/w or about 15.0% w/w and, in particular, in an amount of about 1.5% w/w, about 3.0% w/w, about 4.0% w/w, about 5.0% w/w, about 6.0% w/w, about 7% w/w, about 7.5% w/w, about 8% w/w, about 9.0% w/w, about 10.0% w/w, about 11.0% w/w, about 12.0% w/w, about 13.0% w/w, about 14.0% w/w or about 15.0% w/w.

Formulations

In various embodiments, the present invention is directed to an excipient composition comprising a lecithin powder, a galactomannan, one or more sweetening agents, one or more flavoring agents and an organic acid in a preparation that when combined with an API produces a pharmaceutically acceptable preparation.

The invention utilizes functional excipients to produce a powder such that the following are achieved:

-   -   1. Acceptable properties of flow, density, compactibility,         suspendability, and dispersability are achieved for powder,         solution, and suspension dosage forms.     -   2. Acceptable flavor profiles (intensity of flavor) and         sufficient taste masking of one or more active pharmaceutical         ingredients in the dosage forms listed in item 1 without the         need for complex taste masking methods.     -   3. The same powder formulation can be processed utilizing but         not limited to dry blending, roller compaction, wet granulation,         spheronization and filled into foil/stick packs/sachets/pouches,         compressed into chewable/swallowable/quick dissolving tablets         and filled into capsules.     -   4. The invention allows for the powder dosage form to quickly         dissolve in the mouth or the powder can be readily dissolved or         suspended and dispersed using a small quantity of water and then         taken by mouth.

In various embodiments, the formulation is a dispersion comprising ibuprofen, guar, lecithin, and flavors. In such a dispersion, isomalt, xylitol, citric acid, can be solubilized. In various other embodiments, the formulation can comprise components which are all solubilized.

Lecithin refers to a group of amphiphilic, surfactant compounds naturally occurring in plant and animal tissue and pharmaceutically useful as emulsifying agents. Lecithins can be found in fish, eggs, milk, soybeans, cotton seed, rapeseed and sunflower seeds. Chemically, the central structure of lecithin is a glycerol group with ester linkages to two long chain fatty acid groups and to an orthophosphate group. The orthophosphate group is then linked by an ester bond to a strongly basic choline group (12). The resultant molecule as shown below is a surfactant:

In processing from plant sources, the extract may be in oily liquid form as a result of the presence of liquid oily components which when further removed yields a granular or powder product.

Sunflower lecithin powder contains phosphatidyl choline, phosphatidyl inositol, phosphatidyl ethanolamine, and phosphatidic acid. In contrast to this, lecithin oil additionally contains oily components that result in the composition being in the form of an oily liquid.

The term “lecithin” or “lecithin powder” as used herein is intended to reference lecithin in powder or granular form and not lecithin oil.

The lecithin powder may be present in the excipient composition as well as in compositions containing an API and the excipient composition in an amount of from about 0.1% w/w, about 0.2% w/w, about 0.4% w/w up to about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w or about 1.0% w/w and, in particular, in an amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w or about 1.0% w/w.

The term “galactomannan” refers to a polysaccharide containing a mannose backbone and galactose side groups. Galactomannans may have a mannose to galactose ratio of from about 1:1 to about 4:1 and non-limiting examples include fenugreek gum, guar gum, tara gum and locust bean gum. Guar gum, in particular, may be useful as a component in the formulations herein.

The galactomannan, guar gum (mannose:galactose-2:1) may be present in the excipient composition as well as in compositions containing an API and the excipient composition in an amount of from about 0.05% w/w, about 0.1% w/w, about 0.2% w/w up to about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w or about 0.5% w/w and, in particular, in an amount of about 0.05% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w or about 0.5% w/w.

Sweetening agents such as sugar alcohols, in particular, may be useful in the formulations herein. Sugar alcohols are polyols that may be derived from sugars in which either the aldehyde or the keto group may be reduced. These may include (with chain length indicated in parentheses): glycerol (3-carbon), erythritol (4-carbon), threitol (4-carbon), arabitol (5-carbon), xylitol (5-carbon), ribitol (5-carbon), mannitol (6-carbon), sorbitol, (6-carbon), galactitol (6-carbon), fucitol (6-carbon), iditol (6-carbon), inositol (6-carbon cyclic sugar alcohol), volemitol (7-carbon), isomalt (12-carbon), maltitol (12-carbon), lactitol (12-carbon), maltotriitol (18-carbon) and maltotetraitol (24-carbon). Xylitol and isomalt, in particular, may be useful in the formulations herein. Xylitol may be present in the excipient composition as well as in compositions containing an API and the excipient composition in an amount of from about 1% w/w, about 5% w/w, about 10% w/w or about 15% w/w up to about 25% w/w, about 30% w/w, about 35% w/w or about 40% w/w and, in particular, in an amount of about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35 o about 40% w/w.

Isomalt may be present in the excipient composition as well as in compositions containing an API and the excipient composition in an amount of from about 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w or about 65% w/w up to about 75% w/w, about 80% w/w or about 85% w/w and, in particular, in an amount of about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 85% w/w, or about 90% w/w. Other fillers or diluents can include dextrins, maltodextrins, fructose, and the like in the same amounts. Those of skill in the art will recognize other fillers and diluents suitable in the present formulation.

Flavoring agents may also be included in the formulations herein. Flavoring agents are additives that modify or enhance the taste and the aroma of orally consumed substances. Examples of the flavoring agent that may be used in the formulations herein include fruity flavoring agents such as cherry, strawberry and raspberry as well as other flavoring agents such as peppermint, spearmint, lemon, etc. Cherry, strawberry and raspberry flavorings, in particular, may be useful in the formulations herein.

The cherry, strawberry and raspberry flavoring, may be present in the excipient composition as well as in compositions containing an API and the excipient composition in an amount of from about 0.02% w/w, about 0.04% w/w, about 0.08% w/w, about 0.1% w/w, about 0.2% w/w, about 0.4% w/w, about 0.8% w/w up to about 1.2% w/w, about 1.4% w/w, about 1.6% w/w, about 1.8% w/w or about 2.0% w/w and, in particular, in an amount of about 0.02% w/w, about 0.04% w/w, about 0.08% w/w, about 0.1% w/w, about 0.2% w/w, about 0.4% w/w, about 0.6% w/w, about 0.8% w/w, about 1.0% w/w, about 1.2% w/w, about 1.4% w/w, about 1.6% w/w, about 1.8% w/w, about 2.0% w/w, or about 3% w/w.

The formulations herein may also include an organic acid such as citric acid, tartaric acid, ascorbic acid, fumaric acid, malic acid, adipic acid, succinic acid etc. Citric acid, in particular, may be useful in the formulations herein.

Citric acid may be present in the excipient composition as well as in compositions containing an API and the excipient composition in an amount of from about 0.025% w/w, about 0.05% w/w, about 0.1% w/w up to about 0.15% w/w, about 0.175% w/w, about 0.2% w/w, about 0.225 w/w or about 0.25 w/w and, in particular, in an amount of about 0.025 w/w, about 0.05% w/w, about 0.0755% w/w, about 0.1% w/w, about 0.125% w/w, about 0.15 w/w, about 0.175 w/w, about 0.2% w/w, about 0.225 w/w or about 0.25% w/w. Other acidulants may be included in the present formulation in the same amounts, such as malic acid, formic acid, and the like. Those of skill in the art will recognize other acidulants useful in the present formulation.

The formulations herein may be processed by dry blending, roller compaction, wet granulation, spheronization and filled into foil/stick packs/sachets/pouches, compressed into chewable/swallowable/quick dissolving tablets and filled into capsules.

Examples

Aspects of the present teachings may be further understood in light of the following examples, which should not be construed as limiting the scope of the present teachings in any way. Unless otherwise indicated, the amount of formulation tested was 1.33 g or 2.66 g, which will be identified in the context of the examples below.

Example 1

This example evaluated a prototype formula with Isomalt to ascertain preliminary information on mouth feel, flavor intensity, and sweetness.

TABLE 1a Blend Fill Batch Weight API Batch Weight (mg) (mg) (units) (g) 500.0 100.0 100 50

TABLE 1b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI Group 7050-3921 20.000 100.000 10.000 0.010 USP Isomalt Beneo L1216907U2 79.800 399.000 39.900 0.040 (Galen IQ) GMBH Natural Virginia S79317 0.100 0.500 0.050 0.000 Cherry Dare Flavor CX91 #32839 Edicol 60- Lucid 152/2016 0.100 0.500 0.050 0.000 70 (guar gum) TOTAL 100.000 500.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen and Isomalt through a #20 screen.

2. Screen flavor through a #40 screen.

3. Add the following into a plastic bag in the following order:

-   -   a. ½ Isomalt     -   b. Ibuprofen     -   c. flavor     -   d. Guar gum     -   e. ½ Isomalt

4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

There was no bitter taste in mouth with a little to moderate burn in the throat. Flavor intensity was not enough.

Example 2

This example evaluated a formula with Xylitol to lessen throat burning, increase flavor, and increase sweetness.

TABLE 2a Blend Fill Batch Weight API Batch Weight (mg) (mg) (units) (g) 500.0 100.0 100 50

TABLE 2b Lot % mg/blend g/batch kg/batch Ingredient Vendor Number Concentration fill size size Ibuprofen, SI group 7050-3921 20.000 100.000 10.000 0.010 USP Xylitol Dupont 1942791649 78.900 394.500 39.450 0.039 (Xivia CM170) Natural Virginia S79317 1.000 5.000 0.500 0.001 Cherry Dare Flavor CX91 #32839 Edicol 60-70 Lucid 152/2016 0.100 0.500 0.050 0.000 (guar gum) TOTAL 100.000 500.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen and Xylitol through a #20 screen.

2. Screen flavor through a #40 screen.

3. Add the following into a plastic bag in the following order:

-   -   a. ½ Xylitol     -   b. Ibuprofen     -   c. flavor     -   d. Guar gum     -   e. ½ Xylitol

4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

There was some bitterness in mouth and some burning. Flavor intensity needs to be improved. Sweetness level seemed acceptable. Body may be improved by increasing gum level.

Example 3

This example evaluated a formulation with Xylitol to lessen throat burning and with increased flavor and sweetness components.

TABLE 3a Blend Fill Batch Weight API Batch Weight (mg) (mg) (units) (g) 1,000.0 100.0 50 50

TABLE 3b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 10.000 100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 43.875 438.750 21.938 0.022 (Galen IQ) GMBH Xylitol Dupont 1942791649 43.875 438.750 21.938 0.022 (Xivia CM170) All Natural Virginia S79317 2.000 20.000 1.000 0.001 Cherry Dare Flavor CX91 #32839 Edicol 60-70 Lucid 152/2016 0.250 2.500 0.125 0.000 (guar gum) TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 screen.

3. Add the following into a plastic bag in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. flavor     -   d. Guar gum     -   e. Xylitol

4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

There was very little burning after formulation was completely wetted in the mouth. Sweetness was acceptable. Flavor needs to be more intense. Mouthfeel was acceptable.

When taken wet with 5 g of filtered water, flavor and sweetness was comparable to dry intake with very low level of burning.

This Formula went into solution easily except that the ibuprofen seemed to agglomerate and form a film at the top. The formulation needs a natural surfactant so that the ibuprofen will disperse uniformly into the water.

Example 4

This example evaluated a formulation with a 3:1 ratio of Isomalt to Xylitol and with increased flavor concentration.

TABLE 4a Blend Fill Batch Weight API Batch Weight (mg) (mg) (units) (g) 1,000.0 100.0 50 50

TABLE 4b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 10.000 100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.313 643.130 32.157 0.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.437 214.370 10.719 0.011 (Xivia CM170) All Natural Virginia S79317 4.000 40.000 2.000 0.002 Cherry Dare Flavor CX91 #32839 Edicol 60-70 Lucid 152/2016 0.250 2.500 0.125 0.000 (guar gum) TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 screen.

3. Add the following into a plastic bag in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. flavor     -   d. Guar gum     -   e. Xylitol

4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

Sweetness was acceptable, however it might be desirable to add more sweetener. There was no bitter taste and virtually no burning. Flavor intensity was improved. Mouthfeel was acceptable.

Example 5

This example evaluated the replacement of Virginia Dare (VD) Cherry with Gold Coast (GC) Organic Cherry at the same concentration.

TABLE 5a Blend Fill Batch Weight API Batch Weight (mg) (mg) (units) (g) 1,000.0 100.0 50 50

TABLE 5b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 10.000 100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.313 643.130 32.157 0.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.437 214.370 10.719 0.011 (Xivia CM170) Organic Gold 12/2/2016 4.000 40.000 2.000 0.002 Cherry Coast Flavor #650818 Edicol 60-70 Lucid 152/2016 0.250 2.500 0.125 0.000 (guar gum) TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 screen.

3. Add the following into a plastic bag in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. flavor     -   d. Guar gum     -   e. Xylitol

4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

There was no bitter taste or burning. Cherry flavor is a juicy bright flavor that is very good. Mouthfeel was acceptable and sufficiently sweet.

When taken wet with 5 ml of water, a significant portion of undissolved powder filmed and agglomerated on top of the water surface. Sweetness and flavor intensity was similar to that when taken dry and burning was too apparent.

Example 6

This example compares Strawberry and Raspberry Flavors from VD and GC at the same concentration as Cherry flavoring.

TABLE 6a Blend Fill Batch Weight API Batch Weight (mg) (mg) (units) (g) 1,000.0 100.0 50 50

TABLE 6b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 10.000 100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.313 643.130 32.157 0.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.437 214.370 10.719 0.011 (Xivia CM170) IBU-006-1 All Natural Virginia S79315 4.000 40.000 2.000 0.002 Strawberry Dare Flavor #34775 IBU-006-2 All Natural Virginia S79313 Raspberry Dare Flavor #26507 IBU-006-3 Organic Gold 12/2/2016 Strawberry Coast Flavor #311904 IBU-006-4 Organic Gold 12/2/2016 Raspberry Coast Flavor #325361 Edicol 60- Lucid 152/2016 0.250 2.500 0.125 0.000 70 (guar gum) TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 screen.

3. Add the following into a plastic bag in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. flavor     -   d. Guar gum     -   e. Xylitol

4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

IBU-006-1: Taste was pleasant and not bitter and with very little burning after rinsing mouth with water.

IBU-006-2: Flavor did not taste mask as well as formulation IBU-006-1. Bitterness and burning were apparent. The powder blend had a pink color due to flavoring.

IBU-006-3: Flavor was very pleasant with no bitterness or burning.

IBU-006-4: Flavor was Intense with no bitterness or burning.

Example 7

This example compared VD Cherry-Strawberry to GC Cherry-Strawberry combinations at the same ratio and total concentrations.

TABLE 7a Blend Fill Batch Weight API Batch Weight (mg) (mg) (units) (g) 1,000.0 100.0 50 50

TABLE 7b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 10.000 100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.313 643.130 32.157 0.032 (Galen IQ) GMBH Xylitol (Xivia Dupont 1942791649 21.437 214.370 10.719 0.011 CM170) IBU-007-1 All Natural Virginia S79317 2.000 20.000 1.000 0.001 Cherry Flavor Dare CX91 #32839 All Natural Virginia S79315 2.000 20.000 1.000 0.001 Strawberry Dare Flavor #34775 IBU-007-1 Organic Gold 12/2/2016 2.000 20.000 1.000 0.001 Cherry Flavor Coast #650818 Organic Gold 12/2/2016 2.000 20.000 1.000 0.001 Strawberry Coast Flavor #311904 Edicol 60-70 Lucid 152/2016 0.250 2.500 0.125 0.000 (guar gum) TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 screen.

3. Add the following into a plastic bag in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. flavor     -   d. Guar gum     -   e. Xylitol

4. Blend by rotating the bag at a consistent pace for 3 minutes

Results:

IBU-007-1: With 1 g sample, flavor combination was pleasant with no bitterness and minor burning after completely wetted in the mouth. Strawberry flavor was dominant.

IBU-007-2: With 1 g sample, flavor combination was very good with no burning or bitterness after completely wetted in the mouth. Strawberry flavor was dominant. With larger amount of 2 g, the cherry and strawberry flavors could be detected with no bitterness or burning after complete wetted in the mouth by swishing the suspension around in the mouth.

Example 8

This example compared VD Cherry-Strawberry-Raspberry flavorings to GC Cherry-Strawberry-Raspberry flavorings.

TABLE 8a Blend Fill API Batch Batch Weight (mg) (mg) (units) Weight (g) 1,000.0 100.0 50 50

TABLE 8b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 10.000 100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.313 643.130 32.157 0.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.437 214.370 10.719 0.011 (Xivia CM170) IBU-008-1 All Natural Virginia S79317 1.340 13.400 0.670 0.001 Cherry Dare Flavor CX91 #32839 All Natural Virginia S79315 1.330 13.300 0.665 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.330 13.300 0.665 0.001 Raspberry Dare Flavor #26507 IBU-008-2 Organic Gold 12/2/2016 1.340 13.400 0.670 0.001 Cherry Coast Flavor #650818 Organic Gold 12/2/2016 1.330 13.300 0.665 0.001 Strawberry Coast Flavor #311904 Organic Gold 12/2/2016 1.330 13.300 0.665 0.001 Raspberry Coast Flavor #325361 Edicol 60- Lucid 152/2016 0.250 2.500 0.125 0.000 70 (guar gum) TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 screen.

3. Add the following into a plastic bag in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. flavor     -   d. Guar gum     -   e. Xylitol

4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

IBU-008-1: With 2 g sample, flavor was very pleasant with good balance, spicy after notes, no bitterness and little burning in throat.

IBU-008-2: With 2 g sample, flavor was very pleasant with strawberry dominance, no bitterness and some irritation in throat.

Example 9

This example evaluated Sunflower Lecithin to aid in dispersion of Ibuprofen in suspension form. Also evaluated were a reduced amount of strawberry flavoring.

TABLE 9a Blend Fill API Batch Batch Weight (mg) (mg) (units) Weight (g) 1,000.0 100.0 50 50

TABLE 9b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 10.000 100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.373 643.730 32.187 0.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.457 214.570 10.729 0.011 (Xivia CM170) IBU-009-1 All Natural Virginia S79317 1.340 13.400 0.670 0.001 Cherry Dare Flavor CX91 #32839 All Natural Virginia S79315 1.000 10.000 0.500 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.330 13.300 0.665 0.001 Raspberry Dare Flavor #26507 IBU-009-2 Organic Gold 12/2/2016 1.340 13.400 0.670 0.001 Cherry Coast Flavor #652865 Organic Gold 12/2/2016 1.000 10.000 0.500 0.001 Strawberry Coast Flavor #400938 Organic Gold 12/2/2016 1.330 13.300 0.665 0.001 Raspberry Coast Flavor #325361 Edicol 60- Lucid 152/2016 0.250 2.500 0.125 0.000 70 (guar gum) Sunflower Now None on 0.250 2.500 0.125 0.000 Lecithin container TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. flavor     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

IBU-009-2: With 2 g dry sample, there was good flavor balance with very little drug bitterness or burning.

With 2 g sample in 1 tsp. water, flavor was good with no drug bitterness or burning. Suspension was white, cloudy and uniform.

With 2 g in 2 tsp. water flavor was lighter with adequate sweetness. Suspension was white cloudy, and uniform.

Example 10

This example evaluated a formulation containing GC Cherry with VD Strawberry and Raspberry.

TABLE 10a Blend Fill API Batch Batch Weight (mg) (mg) (units) Weight (g) 1,000.0 100.0 50 50

TABLE 10b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 10.000 100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.126 641.260 32.063 0.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.374 213.740 10.687 0.011 (Xivia CM170) Organic Gold 12/2/2016 1.500 15.000 0.750 0.001 Cherry Coast Flavor #652865 All Natural Virginia S79315 1.000 10.000 0.500 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.500 15.000 0.750 0.001 Raspberry Dare Flavor #26507 Edicol 60- Lucid 152/2016 0.250 2.500 0.125 0.000 70 (guar gum) Sunflower Now None on 0.250 2.500 0.125 0.000 Lecithin container TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 and lecithin through a #100 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. flavor     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2 g dry sample, there was excellent balance of flavor with no bitterness and very low irritation and burning.

With 2 g in 1 tsp. water, the suspension was light pink color and cloudy with a few dark specs coming from raspberry. These dissolved with a little more shaking. Flavor was good with little throat irritation.

With 2 g dry sample swallowed, flavor was excellent with no bitterness and low to moderate throat irritation which went away in a few minutes.

Example 11

This example evaluated a blend with 5% Ibuprofen to reduce or eliminate throat irritation.

TABLE 11a Blend Fill API Batch Batch Weight (mg) (mg) (units) Weight (g) 2,000.0 100.0 25 50

TABLE 11b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 5.000 100.000 2.500 0.003 USP Isomalt Beneo L1216907U2 67.876 1357.520 33.938 0.034 (Galen IQ) GMBH Xylitol Dupont 1942791649 22.624 452.480 11.312 0.011 (Xivia CM170) Organic Gold 12/2/2016 1.500 30.000 0.750 0.001 Cherry Coast Flavor #652865 All Natural Virginia S79315 1.000 20.000 0.500 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.500 30.000 0.750 0.001 Raspberry Dare Flavor #26507 Edicol 60- Lucid 152/2016 0.250 5.000 0.125 0.000 70 (guar gum) Sunflower Now None on 0.250 5.000 0.125 0.000 Lecithin container TOTAL 100.000 2000.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 and lecithin through a #100 screen. (lecithin was difficult to screen through #100).

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. flavor     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 4 g dry sample taste was excellent with no bitterness and virtually no throat irritation. The amount of powder in the mouth was too much.

With 4 g sample in 1 tsp. water, swallowed, the suspension was light pink and cloudy with excellent dispersion and good flavor, good mouthfeel, no bitterness and virtually no irritation.

Example 12

This example evaluated a blend with peppermint at 0.25% to reduce or eliminate throat irritation.

TABLE 12a Blend Fill API Batch Batch Weight (mg) (mg) (units) Weight (g) 1,000.0 100.0 50 50

TABLE 12b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 10.000 100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 63.938 639.380 31.969 0.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.312 213.120 10.656 0.011 (Xivia CM170) Organic Gold 12/2/2016 1.500 15.000 0.750 0.001 Cherry Coast Flavor #652865 All Natural Virginia S79315 1.000 10.000 0.500 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.500 15.000 0.750 0.001 Raspberry Dare Flavor #26507 Organic Gold 12/2/2016 0.250 2.500 0.125 0.000 Peppermint Coast Flavor #315160 Edicol 60- Lucid 152/2016 0.250 2.500 0.125 0.000 70 (guar gum) Sunflower Now None on 0.250 2.500 0.125 0.000 Lecithin container TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. flavor     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2 g dry sample swallowed, there was not enough peppermint which could hardly be detectable and no bitterness, but too much throat burn.

Example 13

This example evaluated a blend with Peppermint at 1% to reduce or eliminate throat irritation.

TABLE 13a Blend Fill API Batch Batch Weight (mg) (mg) (units) Weight (g) 1,000.0 100.0 50 50

TABLE 13b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 10.000 100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 63.375 633.750 31.688 0.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.125 211.250 10.563 0.011 (Xivia CM170) Organic Gold 12/2/2016 1.500 15.000 0.750 0.001 Cherry Coast Flavor #652865 All Natural Virginia S79315 1.000 10.000 0.500 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.500 15.000 0.750 0.001 Raspberry Dare Flavor #26507 Organic Gold 12/2/2016 1.000 10.000 0.500 0.001 Peppermint Coast Flavor #315160 Edicol 60- Lucid 152/2016 0.250 2.500 0.125 0.000 70 (guar gum) Sunflower Now None on 0.250 2.500 0.125 0.000 Lecithin container TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. flavor     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2 g dry sample swallowed, the cool mint and fruit flavor of the combination was excellent with no bitterness and little throat irritation.

Example 14

This example evaluated a blend with 7.5% concentration of Ibuprofen to reduce or eliminate throat irritation.

TABLE 14a Blend Fill API Batch Batch Weight (mg) (mg) (units) Weight (g) 1,333.3 100.0 38.0 50.667

TABLE 14b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 3.800 0.004 USP Isomalt Beneo L1216907U2 66.000 880.000 33.440 0.033 (Galen IQ) GMBH Xylitol Dupont 1942791649 22.000 293.333 11.147 0.011 (Xivia CM170) Organic Gold 12/2/2016 1.500 20.000 0.760 0.001 Cherry Coast Flavor #652865 All Natural Virginia S79315 1.000 13.333 0.507 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.500 20.000 0.760 0.001 Raspberry Dare Flavor #26507 Edicol 60- Lucid 152/2016 0.250 3.333 0.127 0.000 70 (guar gum) Sunflower Now None on 0.250 3.333 0.127 0.000 Lecithin container TOTAL 100.000 1333.333 50.667 0.051

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. flavor     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2.666 g dry sample, swallowed, flavor was excellent with no bitterness and very little throat burning.

With 2.666 g sample in 1 tsp. water, flavor was excellent with no bitterness and no throat burning.

Example 15

This example evaluated an agglomeration blending approach for Ibuprofen and Lecithin with 50:50 ratio of Ibuprofen to Lecithin.

Ibuprofen/Lecithin Agglomeration/Coating/Granulation formulation.

TABLE 15a % Batch Total % Total Solids Weight Coating Lecithin H₂O in H2O (g) (g) in H₂O (g) 82.9 11.000 13.269 70.8 2.269

TABLE 15b % in g/ kg/ Lot Granu- batch batch Ingredient Vendor Number lation size size Ibuprofen, SI 7050- 50.000 5.500 0.006 USP group 3921 Sunflower Now None on 50.000 5.500 0.006 Lecithin container TOTAL 100.000 11.000 0.011

The following process was used.

1. Screen lecithin through #40 screen.

2. Screen Ibuprofen through #20 screen.

3. Blend lecithin and ibuprofen for 3 minutes.

4. Weigh water in Suitable container. Add incrementally with stirring until an agglomeration is achieved.

5. Dry at room temperature until thoroughly dry.

6. Screen granulation through a #20 screen.

Results:

The agglomeration was too elastic too screen into powder.

Example 16

This example evaluated an agglomeration blending approach for ibuprofen and lecithin with 90:10 ratio of ibuprofen to lecithin.

Ibuprofen/Lecithin Agglomeration/Coating/Granulation formulation.

TABLE 16a % Batch Total % in Total Solids Weight Coating Lecithin H₂O in H2O (g) (g) in H₂O (g) 82.7 6.112 7.391 32.3 1.279

TABLE 16b Lot % in g/batch kg/batch Ingredient Vendor Number Granulation size size Ibuprofen, SI group 7050- 90.000 5.501 0.006 USP 3921 Sunflower Now None on 10.000 0.611 0.001 Lecithin container TOTAL 100.000 6.112 0.006

The following process was used.

1. Screen lecithin through #40 screen.

2. Screen Ibuprofen through #20 screen.

3. Blend lecithin and ibuprofen for 3 minutes.

4. Weigh water in Suitable container. Add incrementally with stirring until an agglomeration is achieved.

5. Dry at room temperature until thoroughly dry.

6. Screen granulation through a #20 screen.

Powder Fill Formulation

TABLE 16c Blend Fill Batch Weight API Batch Weight (mg) (mg) (units) (g) 1,000.0 100.0 45 45

TABLE 16d % Lot Granulation % in mg in g/batch kg/batch Ingredient Vendor Number in Blend Blend blend size size Agglomeration-Coating-Granulation Ibuprofen, SI 7050-3921 11.111 10.000 100.000 4.500 0.005 USP group Sunflower Now None on 1.111 11.111 0.500 0.001 Lecithin container TOTAL 111.111 5.000 0.005 Powder Blend Isomalt Beneo L1216907U2 — 63.480 634.800 28.566 0.029 (Galen IQ) GMBH Xylitol Dupont 1942791649 — 21.159 211.590 9.522 0.010 (Xivia CM170) Organic Gold 12/2/2016 — 1.500 15.000 0.675 0.001 Cherry Coast Flavor #652865 All Virginia S79315 — 1.000 10.000 0.450 0.000 Natural Dare Strawberry Flavor #34775 All Virginia S79313 — 1.500 15.000 0.675 0.001 Natural Dare Raspberry Flavor #26507 Edicol 60- Lucid 152/2016 — 0.250 2.500 0.113 0.000 70 (guar gum) TOTAL 100.000 1000.001 45.000 0.045

The blend Process was as follows.

1. Screen Isomalt and Xylitol through a #20 screen.

2. Screen flavors through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen-lecithin granulation     -   d. flavor     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

Blend did not appear uniform. It was screened through a #40 mesh and re-blended for 3 minutes.

With 2 g dry sample, swallowed, there was no bitter, but there was considerable burning on tongue. There was no throat irritation.

Example 17

This example evaluated a blend of 7.5% Ibuprofen with Lecithin at 0.5%.

TABLE 17a Blend Fill Batch Weight API Batch Weight (mg) (mg) (units) (g) 1,333.3 100.0 38.0 50.665

TABLE 17b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI 7050-3921 7.500 100.000 3.800 0.004 USP group Isomalt Beneo L1216907U2 67.550 900.644 34.224 0.034 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 10.032 0.010 (Xivia CM170) Organic Gold 12/2/2016 1.650 21.999 0.836 0.001 Cherry Coast Flavor #652865 All Natural Virginia S79315 1.100 14.666 0.557 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.650 21.999 0.836 0.001 Raspberry Dare Flavor #26507 Edicol 60- Lucid 152/2016 0.250 3.333 0.127 0.000 70 (guar gum) Sunflower Now None on 0.500 6.667 0.253 0.000 Lecithin container TOTAL 100.000 1333.303 50.665 0.051

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. flavor     -   e. Guar gum     -   f Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2.666 g dry sample swallowed, the flavor was intense and sweetness good with no bitterness and very little throat irritation which went away in about 3 minutes.

With 2.666 g sample in 1 tsp. water, sample dispersed easily to yield a pink cloudy dispersion. The flavor was intense with good sweetness with no bitterness and virtually no throat irritation.

Example 18

This example evaluated an agglomeration blending approach for Ibuprofen and Lecithin with 90:10 ratio of Ibuprofen to Lecithin.

Ibuprofen/Lecithin Agglomeration/Coating/Granulation formulation.

TABLE 18a % Batch Total % Solids Weight Coating Lecithin Total in H2O (g) (g) in H₂O H₂O (g) 100.0 7.000 7.000 100.0 0.000

TABLE 18b Lot % in g/batch kg/batch Ingredient Vendor Number Granulation size size Ibuprofen, SI 7050- 80.000 5.600 0.006 USP group 3921 Sunflower Now None on 20.000 1.400 0.001 Lecithin container TOTAL 100.000 7.000 0.007

The following process was used.

1. Screen lecithin through #40 screen.

2. Screen Ibuprofen through #20 screen.

3. Blend lecithin and ibuprofen for 3 minutes.

4. Weigh water in Suitable container. Add incrementally with stirring until an agglomeration is achieved.

5. Dry at room temperature until thoroughly dry.

6. Screen granulation through a #40 screen.

Results.

Agglomeration tastes very bitter. so that blend with additional components was not made.

Example 19

This example evaluated an agglomeration blending approach for Ibuprofen and Lecithin with 50:50 ratio of Ibuprofen to Lecithin using a low quantity of water.

Ibuprofen/Lecithin Agglomeration/Coating/Granulation formulation.

TABLE 19a % Batch Total % Total Solids Weight Coating Lecithin H₂O in H₂O (g) (g) in H₂O (g) 100.00 14.000 14.000 100.0 0.000

TABLE 19b Lot % in g/batch kg/batch Ingredient Vendor Number Granulation size size Ibuprofen, SI 7050-3921 50.000 7.000 0.007 USP group Sunflower Now None on 50.000 7.000 0.007 Lecithin container TOTAL 100.000 14.000 0.014

The following process was used.

1. Screen lecithin through #40 screen.

2. Screen Ibuprofen through #20 screen.

3. Blend lecithin and ibuprofen for 3 minutes.

4. Weigh water in Suitable container. Add incrementally with stirring until an agglomeration is achieved (0.471 g H₂O).

5. Dry at room temperature until thoroughly dry.

6. Screen granulation.

Results:

400 mg agglomeration was swallowed dry with some bitterness and a little throat irritation detected.

Granules were too soft and no further blending was done.

Example 20

This example evaluated 7.5% formulation with Citric Acid at 0.5%, 0.25% and 0.125%.

TABLE 20a Bulk Blend. (IBU-20) Blend Fill Weight API Batch Batch (mg) (mg) (units) Weight (g) 1,333.3 100.0 38.0 50.665

TABLE 20b Bulk Blend. (IBU-20). % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 3.800 0.004 USP Isomalt Beneo L1216907U2 67.550 900.644 34.224 0.034 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 10.032 0.010 (Xivia CM170) Organic Gold 12/2/2016 1.650 21.999 0.836 0.001 Cherry Coast Flavor #652865 All Natural Virginia S79315 1.100 14.666 0.557 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.650 21.999 0.836 0.001 Raspberry Dare Flavor #26507 Edicol 60- Lucid 152/2016 0.250 3.333 0.127 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.253 0.000 20 GMBH 2160013 Sunflower Lecithin TOTAL 100.000 1333.303 50.665 0.051

The following process was used.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. flavor     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

TABLE 20c Citric Acid 0.5% (IBU-20-1). Blend Fill Weight API Batch Batch (mg) (mg) (units) Weight (g) 1,333.3 100.0 7.5 10.000

TABLE 20d Citric Acid 0.5% (IBU-20-1). % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 0.750 0.001 USP Isomalt Beneo L1216907U2 67.050 893.978 6.705 0.007 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 1.980 0.002 (Xivia CM170) Organic Gold 12/2/2016 1.650 21.999 0.165 0.000 Cherry Coast Flavor #652865 All Virginia S79315 1.100 14.666 0.110 0.000 Natural Dare Strawberry Flavor #34775 All Virginia S79313 1.650 21.999 0.165 0.000 Natural Dare Raspberry Flavor #26507 Edicol 60- Lucid 152/2016 0.250 3.333 0.025 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.050 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.500 6.667 0.050 0.000 Almonds TOTAL 100.000 1333.303 10.000 0.010

TABLE 20e Citric Acid at 0.25% (IBU-20-2). Blend Fill Weight API Batch Batch (mg) (mg) (units) Weight (g) 1,333.3 100.0 7.5 10.000

TABLE 20f Citric Acid at 0.25% (IBU-20-2) % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 0.750 0.001 USP Isomalt Beneo L1216907U2 67.300 897.311 6.730 0.007 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 1.980 0.002 (Xivia CM170) Organic Gold 12/2/2016 1.650 21.999 0.165 0.000 Cherry Coast Flavor #652865 All Virginia S79315 1.100 14.666 0.110 0.000 Natural Dare Strawberry Flavor #34775 All Virginia S79313 1.650 21.999 0.165 0.000 Natural Dare Raspberry Flavor #26507 Edicol 60- Lucid 152/2016 0.250 3.333 0.025 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.050 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.250 3.333 0.025 0.000 Almonds TOTAL 100.000 1333.303 10.000 0.010

TABLE 20g Citric Acid at 0.125% (IBU-20-3). Blend Fill Weight API Batch Batch (mg) (mg) (units) Weight (g) 1,333.3 100.0 7.5 10.000

TABLE 20h Citric Acid at 0.125% (IBU-20-3). % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 0.750 0.001 USP Isomalt Beneo L1216907U2 67.425 898.978 6.742 0.007 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 1.980 0.002 (Xivia CM170) Organic Gold 12/2/2016 1.650 21.999 0.165 0.000 Cherry Coast Flavor #652865 All Virginia S79315 1.100 14.666 0.110 0.000 Natural Dare Strawberry Flavor #34775 All Virginia S79313 1.650 21.999 0.165 0.000 Natural Dare Raspberry Flavor #26507 Edicol 60- Lucid 152/2016 0.250 3.333 0.025 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.050 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.125 1.667 0.012 0.000 Almonds TOTAL 100.000 1333.303 10.000 0.010

The blending process was as follows.

1. Weigh a 10 g portion of the bulk blend.

2. Screen Citric Acid through a #40 screen.

3. Blend citric acid with the bulk blend for 1 minute.

TABLE 20i Citric Acid at 0.125% and increased flavorings (IBU-20-4). Blend Fill Weight Batch Batch (mg) API (mg) (units) Weight (g) 1,356.2 100.0 7.5 10.172

TABLE 20j Citric Acid at 0.125% and increased flavorings (IBU-20-4). % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.374 100.000 0.750 0.001 USP Isomalt Beneo L1216907U2 65.951 894.427 6.708 0.007 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 268.528 2.014 0.002 (Xivia CM170) Organic Gold 12/2/2016 2.000 27.124 0.203 0.000 Cherry Coast Flavor #652865 All Virginia S79315 2.000 27.124 0.203 0.000 Natural Dare Strawberry Flavor #34775 All Virginia S79313 2.000 27.124 0.203 0.000 Natural Dare Raspberry Flavor #26507 Edicol 60- Lucid 152/2016 0.250 3.391 0.025 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.781 0.051 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.125 1.695 0.013 0.000 Almonds TOTAL 100.000 1356.194 10.171 0.010

The Blend process was as follows.

1. Weigh a 10 g portion of the bulk blend.

2. Screen flavors through a #40 and add the difference.

-   -   Cherry: 0.035     -   Strawberry: 0.09     -   Raspberry: 0.035

3. Screen Citric Acid through a #40 screen.

4. Blend Flavors and Citric Acid for 1 minute.

TOTAL Weight=10.172 g

Results:

Citric Acid from 0.5-0.25% was too sour.

Citric Acid at 0.125% (IBU-020-3) lessens the sour flavor but does bring out the fruit complex.

IBU-20-4:

With 2.712 g dry sample, flavor was very intense with a little spice note. Sample was not sour, but brought out a little bit of tartness. Although not swallowed; there was a little bit of throat irritation.

With 2.712 g sample in 1 tsp water, swallowed, flavor and sweetness were excellent with no bitterness or throat irritation.

Example 21

This example repeats the IBU-020-4 formulation in Example 29 at a 50 g batch weight.

TABLE 21a Citric Acid at 0.125% Blend Fill API Batch Batch Weight (mg) (mg) (units) Weight (g) 1,333.3 100.0 38.0 50.665

TABLE 21b Citric Acid at 0.125%, % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 3.800 0.004 USP Isomalt Beneo L1216907U2 65.825 877.645 33.350 0.033 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 10.032 0.010 (Xivia CM170) Organic Gold 12/2/2016 2.000 26.666 1.013 0.001 Cherry Coast Flavor #652865 All Virginia S79315 2.000 26.666 1.013 0.001 Natural Dare Strawberry Flavor #34775 All Virginia S79313 2.000 26.666 1.013 0.001 Natural Dare Raspberry Flavor #26507 Edicol 60- Lucid 152/2016 0.250 3.333 0.127 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.253 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.125 1.667 0.063 0.000 Almonds TOTAL 100.000 1333.303 50.665 0.051

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor and citric acid through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. Flavors     -   e. Citric acid     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2.666 g dry sample, swallow flavor and sweetness were excellent with no bitterness and very little throat irritation.

With 2.666 g sample in 1 tsp. water, swallowed, flavor and sweetness were excellent with no bitterness and no throat irritation.

Example 22

This example evaluated the formula in example 21, but with a 25% reduction in flavor components.

TABLE 22a Blend Fill Weight API Batch Batch Weight (mg) (mg) (units) (g) 1,333.3 100.0 38.0 50.665

TABLE 22b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 3.800 0.004 USP Isomalt Beneo L1216907U2 67.325 897.644 34.110 0.034 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 10.032 0.010 (Xivia CM170) Organic Gold 12/2/2016 1.500 20.000 0.760 0.001 Cherry Coast Flavor #652865 All Virginia S79315 1.500 20.000 0.760 0.001 Natural Dare Strawberry Flavor #34775 All Virginia S79313 1.500 20.000 0.760 0.001 Natural Dare Raspberry Flavor #26507 Edicol 60- Lucid 152/2016 0.250 3.333 0.127 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.253 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.125 1.667 0.063 0.000 Almonds TOTAL 100.000 1333.303 50.665 0.051

The blend Process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor and citric acid through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. Flavors     -   e. Citric acid     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2.666 g dry sample, swallowed, flavor intensity and sweetness were good with light spicy flavor, no bitterness and little throat irritation.

With 2.666 g sample 1 tsp. water, flavor intensity and sweetness were good with no bitterness and no throat irritation.

Example 23

This example evaluated a formulation with reduced flavor components (33% reduction compared to example 22).

TABLE 23a Blend Fill Weight API Batch Batch Weight (mg) (mg) (units) (g) 1,333.3 100.0 38.0 50.665

TABLE 23b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 3.800 0.004 USP Isomalt Beneo L1216907U2 68.825 917.644 34.870 0.035 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 10.032 0.010 (Xivia CM170) Organic Gold 12/2/2016 1.000 13.333 0.507 0.001 Cherry Coast Flavor #652865 All Virginia S79315 1.000 13.333 0.507 0.001 Natural Dare Strawberry Flavor #34775 All Virginia S79313 1.000 13.333 0.507 0.001 Natural Dare Raspberry Flavor #26507 Edicol 60- Lucid 152/2016 0.250 3.333 0.127 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.253 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.125 1.667 0.063 0.000 Almonds TOTAL 100.000 1333.303 50.665 0.051

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor and citric acid through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. Flavors     -   e. Citric acid     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2.666 g dry sample, swallowed, flavor intensity and sweetness were good with no bitterness and little throat irritation

With 2.666 g sample in 1 tsp. water, flavor intensity and sweetness were good with no bitterness and no throat irritation.

Example 24

This example evaluated a formulation with a change in Cherry flavoring supplier from GC to VC.

TABLE 24a Blend Fill Weight API Batch Batch Weight (mg) (mg) (units) (g) 1,333.3 100.0 38.0 50.665

TABLE 25b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 3.800 0.004 USP Isomalt Beneo L1216907U2 68.825 917.644 34.870 0.035 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 10.032 0.010 (Xivia CM170) All Virginia S79579 1.000 13.333 0.507 0.001 Natural Dare Cherry Flavor #34327 All Virginia S79315 1.000 13.333 0.507 0.001 Natural Dare Strawberry Flavor #34775 All Virginia S79313 1.000 13.333 0.507 0.001 Natural Dare Raspberry Flavor #26507 Edicol 60- Lucid 152/2016 0.250 3.333 0.127 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.253 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.125 1.667 0.063 0.000 Almonds TOTAL 100.000 1333.303 50.665 0.051

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor and citric acid through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. Flavors     -   e. Citric acid     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2.666 g dry sample swallowed, flavor and sweetness were excellent with no bitterness and very little throat irritation.

With 2.666 g sample in 1 tsp. water, flavor and sweetness were excellent with no bitterness and no throat irritation. Overall the VD Cherry flavor is equal or superior to the GC cherry.

Example 25

This example evaluated a change from VD raspberry (color) to VD raspberry (colorless). Otherwise all conditions were the same as in example 24.

TABLE 25a Blend Fill Weight API Batch Batch Weight (mg) (mg) (units) (g) 1,333.3 100.0 38.0 50.665

TABLE 25b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 3.800 0.004 USP Isomalt Beneo L1216907U2 68.825 917.644 34.870 0.035 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 10.032 0.010 (Xivia CM170) All Virginia S79579 1.000 13.333 0.507 0.001 Natural Dare Cherry Flavor #34327 All Virginia S79315 1.000 13.333 0.507 0.001 Natural Dare Strawberry Flavor #34775 All Virginia S79313 1.000 13.333 0.507 0.001 Natural Dare Raspberry Flavor #20625 Edicol 60- Lucid 152/2016 0.250 3.333 0.127 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.253 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.125 1.667 0.063 0.000 Almonds TOTAL 100.000 1333.303 50.665 0.051

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor and citric acid through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. Flavors     -   e. Citric acid     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2.666 g dry sample, the raspberry flavor was too strong with a volatile essence.

Example 26

This example evaluated a formulation with VD Raspberry (colorless) in an amount (0.5%).

TABLE 26a Blend Fill Weight API Batch Batch Weight (mg) (mg) (units) (g) 1,333.3 100.0 38.0 50.665

TABLE 26b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 3.800 0.004 USP Isomalt Beneo L1216907U2 69.325 924.310 35.124 0.035 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 10.032 0.010 (Xivia CM170) All Virginia S79579 1.000 13.333 0.507 0.001 Natural Dare Cherry Flavor #34327 All Virginia S79315 1.000 13.333 0.507 0.001 Natural Dare Strawberry Flavor #34775 All Virginia S79577 0.500 6.667 0.253 0.000 Natural Dare Raspberry Flavor #20625 Edicol 60- Lucid 152/2016 0.250 3.333 0.127 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.253 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.125 1.667 0.063 0.000 Almonds TOTAL 100.000 1333.303 50.665 0.051

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor and citric acid through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. Flavors     -   e. Citric acid     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2.666 g dry sample, swallowed, flavor was much improved with the raspberry much less overwhelming over the other flavors compared to example 25 and with a little bit of volatile essence through the nose.

Example 27

This example evaluated a formulation with VD Raspberry (colorless) in an amount (0.25%).

TABLE 27a Blend Fill Weight API Batch Batch Weight (mg) (mg) (units) (g) 1,333.3 100.0 38.0 50.665

TABLE 27b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 3.800 0.004 USP Isomalt Beneo L1216907U2 69.575 927.643 35.250 0.035 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 10.032 0.010 (Xivia CM170) All Virginia S79579 1.000 13.333 0.507 0.001 Natural Dare Cherry Flavor #34327 All Virginia S79315 1.000 13.333 0.507 0.001 Natural Dare Strawberry Flavor #34775 All Virginia S79577 0.250 3.333 0.127 0.000 Natural Dare Raspberry Flavor #20625 Edicol 60- Lucid 152/2016 0.250 3.333 0.127 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.253 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.125 1.667 0.063 0.000 Almonds TOTAL 100.000 1333.303 50.665 0.051

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor and citric acid through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. Flavors     -   e. Citric acid     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2.666 g dry sample, swallowed, raspberry flavor was a little too intense with spice note and no volatile essence or bitterness and little throat irritation.

Example 28

This example evaluated a formulation with VD Raspberry (colorless) in an amount of 0.1%.

TABLE 28a Blend Fill Weight API Batch Batch Weight (mg) (mg) (units) (g) 1,333.3 100.0 38.0 50.665

TABLE 28b % mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.000 3.800 0.004 USP Isomalt Beneo L1216907U2 69.725 929.643 35.326 0.035 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 10.032 0.010 (Xivia CM170) All Virginia S79579 1.000 13.333 0.507 0.001 Natural Dare Cherry Flavor #34327 All Virginia S79315 1.000 13.333 0.507 0.001 Natural Dare Strawberry Flavor #34775 All Virginia S79577 0.100 1.333 0.051 0.000 Natural Dare Raspberry Flavor #20625 Edicol 60- Lucid 152/2016 0.250 3.333 0.127 0.000 70 (guar gum) Lipoid H Lipoid 536900- 0.500 6.667 0.253 0.000 20 GMBH 2160013 Sunflower Lecithin Citric Acid Anthony's 5/16/2019 0.125 1.667 0.063 0.000 Almonds TOTAL 100.000 1333.303 50.665 0.051

The blend process was as follows.

1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.

2. Screen flavor and citric acid through a #40 and lecithin through a #40 screen.

3. Add the following into a plastic cup in the following order:

-   -   a. Isomalt     -   b. Ibuprofen     -   c. Lecithin     -   d. Flavors     -   e. Citric acid     -   e. Guar gum     -   f. Xylitol

4. Blend by rotating the plastic cup at a consistent pace for 3 minutes.

Results:

With 2.666 g dry sample swallowed, flavor intensity was at the right level, but Raspberry was still dominating other flavors with no bitterness and little throat irritation

With 2.666 g sample in 1 tsp. water and no swallowing, flavor intensity was good.

Example 29

This example evaluated an ibuprofen powder blend compacted into a tablet. This is from the same formula as example 28 with the addition of 1% Magnesium Stearate added as a lubricant. The target weight of 1.333 g of powder contains a target dose of 100 mg of ibuprofen. Tablets were compressed on a rotary tablet press.

TABLE 29a Avg. Applied Force Tablet Weight (g) Statistics (kN) No. 1 No. 2 No. 3 No. 4 No.5 No. 6 Avg. % RSD 3.68 1.336 1.340 1.338 1.33 1.325 1.327 1.333 0.4 4.64 1.325 1.321 1.33 1.322 1.338 1.337 1.329 0.5 5.50 1.322 1.329 1.331 1.333 1.338 1.328 1.330 0.4 7.00 1.335 1.329 1.338 1.332 1.331 1.325 1.332 0.3 8.16 1.338 1.341 1.336 1.337 1.342 1.344 1.340 0.2 9.24 1.344 1.358 1.355 1.346 1.348 1.344 1.349 0.4 11.18 1.364 1.360 1.364 1.350 1.348 1.370 1.359 0.6

TABLE 29b Avg. Applied Force Tablet Thickness (mm) Statistics (kN) No. 1 No. 2 No. 3 No. 4 No.5 No. 6 Avg. % RSD 3.68 5.72 5.68 5.67 5.65 5.62 5.59 5.66 0.7 4.64 5.48 5.47 5.48 5.49 5.48 5.47 5.48 0.1 5.50 5.34 5.44 5.40 5.35 5.35 5.36 5.37 0.7 7.00 5.23 5.15 5.16 5.17 5.23 5.23 5.20 0.7 8.16 5.12 5.07 5.08 5.08 5.09 5.08 5.09 0.3 9.24 4.98 5.02 4.98 4.96 4.94 4.91 4.97 0.7 11.18 4.86 4.84 4.85 4.87 4.86 4.90 4.86 0.4

TABLE 29c Avg. Applied Force Diametrical Breaking Force (N) Statistics (kN) No. 1 No. 2 No. 3 No. 4 No. 5 No. 6 Avg. % RSD 3.68 11 16 14 14 15 16 14 11.9 4.64 18 16 19 17 18 17 18 5.5 5.50 19 22 24 21 20 25 22 9.7 7.00 30 31 31 27 30 30 30 4.5 8.16 35 39 38 36 34 38 37 4.9 9.24 44 34 44 43 43 45 42 8.8 11.18 51 51 52 48 48 51 50 3.1

TABLE 29d Avg. Applied Force Diametrical Breaking Force (kp) Statistics (kN) No. 1 No. 2 No. 3 No. 4 No. 5 No. 6 Avg. % RSD 3.68 1.1 1.6 1.4 1.4 1.5 1.6 1.5 11.9 4.64 1.8 1.6 1.9 1.7 1.8 1.7 1.8 5.5 5.50 1.9 2.2 2.4 2.1 2.0 2.5 2.2 9.7 7.00 3.1 3.2 3.2 2.8 3.1 3.1 3.0 4.5 8.16 3.6 4.0 3.9 3.7 3.5 3.9 3.7 4.9 9.24 4.5 3.5 4.5 4.4 4.4 4.6 4.3 8.8 11.18 5.2 5.2 5.3 4.9 4.9 5.2 5.1 3.1

The Ibuprofen powder blend was compacted using the following tablet tooling: 18 mm round, flat-face tooling according to Table 29A. The resultant thicknesses of the compacted tablets are provided in Table 29B, and the diametrical breaking forces of the resultant tablets are provided in Tables 29C and 29D.

The data demonstrates that chewable, swallowable and/or orally disintegrating tablets can be produced with good weight control, acceptable thickness and breaking force.

This formula with the magnesium stearate is functional for the dry powder dosage form, suspension dosage form and the chewable tablet. Those of skill in the art will recognize the other lubricants including but not limited to stearic acid, calcium stearate, sodium stearate, sodium stearyl fumarate (PRUV®), talc, and hydrogenated soybean oil (STEROTEX®) can be used in the formula.

Other Embodiments

The detailed description set-forth above is provided to aid those skilled in the art in practicing the present invention. However, the invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.

REFERENCES CITED

All publications, patents, patent applications and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention.

PUBLICATIONS INCORPORATED HEREIN BY REFERENCE IN THEIR ENTIRETY INCLUDE

-   1. Sabaté E. Adherence to Long Term Therapies: Evidence for Action.     World Health Organization. 2003. Available at:     http://apps.who.int/medicinedocs/pdf/s4883e/s4883e.pdf. -   2. Fass R., et al., Pharmacokinetic comparison of     orally-disintegrating metoclopramide with conventional     metoclopramide tablet formulation in healthy volunteers, (2009)     Aliment Pharmacol Ther 30, 301-306. -   3. Mennella, J A et al., The Bad Taste of Medicines: Overview of     Basic Research on Bitter Taste, Clin Ther (2013) 35:1225-1246. -   4. Walsh, J et al., Playing hide and seek with poorly tasting     paediatric medicines: Do not forget the excipients, Advanced Drug     Delivery Reviews (2014) 73: 14-33. -   5. Kanabar, D. J., A clinical and safety review of paracetamol and     ibuprofen in children, Inflammopharmacol (2017) 25:1-9; 6. -   6. Kelley, B. P., Ibuprofen does not increase bleeding risk in     plastic surgery: a systematic review and meta-analysis, Plast     Reconstr Surg, (2016) 137:1309-1316. -   7. Khalifa, N., et al., Use of ibuprofen sustained release for     treating osteoarthritic pain: findings from 15 general medical     practices in Egypt, Rheumatology: Research and Reviews (2014)     6:49-56. -   8. de Klerk E., Patient compliance in rheumatoid arthritis,     polymyalgia rheumatica, and gout, J Rheumatol, (2003) 30:44-54. -   9. Rainsford K D, Ibuprofen: pharmacology, efficacy and safety,     Inflammopharmacology. (2009) 7:275-342. -   10. Rockwell W B and Ehrlich H P. Ibuprofen in acute-care therapy,     Ann Surg. (1990) 211:78-83. -   11. Shin et al., Pharmacokinetic and pharmacodynamic evaluation     according to absorption differences in three formulations of     ibuprofen, Drug Des Devel Ther. (2017) 11: 135-141. -   12. Elworthy P H, et al., The Physical Chemistry of Lecithins, J     Pharmacy Pharmacol (1956) 8: 1001-1018. 

1. A free flowing dry powder oral formulation suitable for administration in each of an aqueous solution, aqueous dispersion, tablet, and powder dosage form, wherein the formulation comprises an active pharmaceutical ingredient (API) in an amount from about 1.5% w/w to about 20% w/w, a lecithin powder in an amount from about 0.1% w/w to about 1% w/w, a galactomannan in an amount from about 0.05% w/w to about 0.5% w/w, one or more sweetening agents in amounts from about 1.0% w/w to about 90% w/w, one or more flavoring agents in an amount from about 0.5% w/w to about 5% w/w and an organic acid in an amount from about 0.05% w/w to about 0.5% w/w, in a pharmaceutically acceptable preparation.
 2. The formulation of claim 1, wherein the API is ibuprofen; the lecithin powder is a sunflower lecithin powder; the galactomannan is guar gum; the one or more sweetening agents are one or more sugar alcohols selected from the group consisting of glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol and maltotetraitol and combinations thereof; the one or more flavoring agents are selected from the group consisting of cherry flavoring, strawberry flavoring, raspberry flavoring, grape flavoring, orange flavoring, other fruit flavors, and combinations thereof and the organic acid is citric acid, malic acid, fumaric acid, any other acidulants, and combinations thereof.
 3. The formulation of claim 2 comprising ibuprofen at about 7.5% w/w, sunflower lecithin at about 0.5% w/w, guar gum at about 0.25% w/w, xylitol at about 19.8%, w/w, isomalt at about 68.8% w/w, cherry flavoring at about 1% w/w, strawberry flavoring at about 1% w/w, raspberry flavoring at about 1% w/w and citric acid at about 0.125% w/w in a pharmaceutically acceptable preparation.
 4. The formulation of claim 2, wherein the formulation solubility or dispersability in water is no more than about 0.5 w/v.
 5. The formulation of claim 2, wherein the formulation is in a unit dosage container selected from the group consisting of a blister foil pack, stick pack, sachet, pouch, or bottle.
 6. The formulation of claim 2, wherein the unit dosage form of ibuprofen is in an amount of about 50, about 75, about 100, about 200, about 400, about 600 or about 800 mg.
 7. A method of preparing a dry powder oral formulation of an API suitable for administration in each of an aqueous solution, aqueous dispersion, tablet, and powder dosage form, the method comprising, combining, in any order, a. an API in an amount from about 1.5% w/w to about 20% w/w, b. a lecithin powder in an amount from about 0.1% w/w to about 1% w/w, c. a galactomannan in an amount from about 0.05% w/w to about 0.5% w/w, d. one or more sweetening agents in an amount from about 1.0% w/w to about 90% w/w, e. one or more flavoring agents in an amount from about 0.5% w/w to about 5% w/w, and f. an organic acid in an amount from about 0.05% w/w to about 0.5% w/w in a pharmaceutically acceptable preparation.
 8. The method of claim 7, wherein the API is ibuprofen; the lecithin powder is sunflower lecithin powder; the galactomannan is guar gum; the one or more sweetening agents are one or more sugar alcohols selected from the group consisting of glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol and combinations thereof; the one or more flavoring agents are selected from the group consisting of cherry flavoring, strawberry flavoring, raspberry flavoring and combinations thereof; and the organic acid is citric acid.
 9. The method of claim 8 comprising ibuprofen at about 7.5% w/w, sunflower lecithin at about 0.5% w/w, guar gum at about 0.25% w/w, xylitol at about 19.8% w/w, isomalt at about 68.8% w/w, cherry flavoring at about 1% w/w, strawberry flavoring at about 1% w/w, raspberry flavoring at about 1% w/w and citric acid at about 0.125% w/w in a pharmaceutically acceptable preparation.
 10. The method of claim 8, wherein the unit dosage form of ibuprofen is in an amount of about 50, about 75, about 100, about 200, about 400, about 600 or about 800 mg.
 11. An excipient composition for combining with an API suitable for administration in a dosage form selected from one of an aqueous solution, aqueous dispersion, tablet, or powder, wherein the excipient composition is used to produce a drug or nutraceutical, the composition comprising a lecithin powder in an amount from about 0.1% w/w to about 1% w/w, a galactomannan in an amount from about 0.05% w/w to about 0.5% w/w, one or more sweetening agents in an amount from about 1.0% w/w to about 90% w/w, one or more flavoring agents in an amount from about 0.5% w/w to about 5% w/w and an organic acid in an amount from about 0.05% w/w to about 0.5% w/w, in a preparation that when combined with an API produces a pharmaceutically acceptable preparation.
 12. The excipient composition of claim 11, wherein the lecithin is a sunflower lecithin powder; the galactomannan is guar gum; the one or more sweetening agents are one or more sugar alcohols selected from the group consisting of glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol and combinations thereof; the one or more flavoring agents are selected from the group consisting of cherry flavoring, strawberry flavoring, raspberry flavoring and combinations thereof and the organic acid is citric acid.
 13. The excipient composition of claim 12 comprising sunflower lecithin at about 0.5% w/w, guar gum at about 0.25% w/w, xylitol at about 68.8% w/w, isomalt at about 19.8% w/w, cherry flavoring at about 1% w/w, strawberry flavoring at about 1% w/w, raspberry flavoring at about 1% w/w and citric acid at about 0.125% w/w in a pharmaceutically acceptable preparation.
 14. The excipient composition of claim 12, wherein the formulation is in a unit dosage form in a container selected from the group consisting of a blister foil pack, stick pack, sachet, pouch, or bottle.
 15. (canceled)
 16. (canceled)
 17. (canceled)
 18. (canceled)
 19. (canceled)
 20. (canceled)
 21. A composition for oral administration of an API to someone in need thereof, wherein the composition is suitable for dosage forms including aqueous solution or dispersion, tablet, chewable tablet, orally disintegrating tablet, dispersible tablet, powder in a capsule, or spheres in a capsule, and wherein the composition comprises an active pharmaceutical ingredient (API) at about 7.5% w/w, a lecithin powder at about 0.5% w/w, a galactomannan at about 0.25% w/w, one or more sweetening agents at about 19% to 70% w/w for each sweeting agent, one or more flavoring agents at about 1% w/w for each flavoring agent, and an organic acid at about 0.125% w/w in a pharmaceutically acceptable preparation.
 22. The composition of claim 21, wherein the API is ibuprofen; the lecithin powder is a sunflower lecithin powder and soy lecithin powder; the galactomannan is guar gum; the one or more sweetening agents are one or more sugar alcohols selected from the group consisting of glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol and maltotetraitol and combinations thereof; the one or more flavoring agents are selected from the group consisting of cherry flavoring, strawberry flavoring, raspberry flavoring, grape flavoring, orange flavoring, other fruit flavors, and combinations thereof; and the organic acid is citric acid, malic acid, fumaric acid, any other acidulants, and combinations thereof.
 22. An excipient composition for combining with an API for oral administration to someone in need thereof, to produce a drug or nutraceutical composition suitable for multiple dosage forms, wherein the dosage forms include aqueous solution or dispersion, tablet, chewable tablet, orally disintegrating tablet, dispersible tablet, powder in a capsule, or spheres in a capsule, the composition comprising a lecithin powder at about 0.1% w/w to 1% w/w, a galactomannan at about 0.05% to about 0.5% w/w, one or more sweetening agents at about 19% to 70% w/w for each sweetening agent, one or more flavoring agents at about 0.5% w/w to about 5% w/w for each flavoring agent, and an organic acid at about 0.05% w/w to about 0.5% w/w in a preparation that when combined with an API produces a pharmaceutically acceptable preparation.
 23. A composition which may be formulated in each of a solution, suspension, powder, and tablet, the composition comprising an active pharmaceutical ingredient (API), a lecithin powder, a galactomannan, one or more sweetening agents, one or more flavoring agents, and an organic acid in a pharmaceutically acceptable preparation.
 24. The composition of claim 23, wherein the composition may be administered to a subject in need thereof in any dosage form selected from a solution, suspension, powder, or tablet.
 25. The composition of claim 23, wherein the powder is a free flowing powder for unit dosage packaging. 